Permanently bonded antithrombogenic polyurethane surface

ABSTRACT

An antithrombogenic polyurethane polymer being bound to a support substrate wherein the antithrombogenic agent is reacted through an aldehyde group with an amine functionality of a polyurethane-urea to form the covalently bonded antithrombogenic material.

This is a divisional of application Ser. No. 718,664 filed Apr. 1, 1985,now U.S. Pat. No. 4,600,652.

The present invention relates to a novel antithrombogenic polyurethanepolymer and process for making the same. More particularly the inventionrelates to a polyurethane polymer having an antithrombogenic materialcovalently bonded thereto so that the material is permanently affixed tothe polymer and remains virtually nonleachable when the products madefrom the reaction product are in use.

Extensive investigations have been undertaken over many years to findmaterials that will be biologically and chemically stable towards bodyfluids. This area of research has become increasingly important with thedevelopment of various objects and articles which can be in contact withblood, such as artificial organs, vascular grafts, probes, cannulas,catheters and the like.

Artificial materials are being increasingly used as blood contactdevices and may be subject to potential generation of thrombus. Whenblood contacts a foreign material, a complex series of events occur.These involve protein deposition, cellular adhesion and aggregation, andactivation of blood coagulation schemes. Considerable research efforthas been focused on this blood-material-interaction in the last twentyyears. The overall objective of these investigations has been tominimize the potential for thrombus formation on the foreign materials,such as the device when introduced into the body upon contact withblood.

Early work by R. I. Leininger and R. D. Falb, U.S. Pat. No. 3,167,344,was based on binding quaternary amines to a polymer surface andsubsequently ionically binding heparin thereto. In contrast, H. M.Grotta established a method in U.S. Pat. No. 3,846,353 in which heparinwas complexed with a quaternary amine on a polymer surface. Both theLeininger et al. and Grotta methods have the disadvantage of beingnon-permanent or leachable systems. In general, ionically bound systemshave limited viability due to their inherent leachability. J. Love andG. W. Holmes patented a method for the preparation of antithrombogenicsurfaces in U.S. Pat. No. 3,616,935 wherein polyalkylenimines are usedto irreversibly absorb the antithrombogenic compound to cellulose,cellulose esters, silicone rubber, polypropylene, polycarbonate andglass through the formation of ionic bonds. The Love et al. technique,however, was not able to overcome the deficiencies of the priortechniques, notably leaching of the antithrombogenic material renderingthe system non-permanent and ineffective for long term internal use inthe body.

U.S. Pat. No. 3,826,678 of A. S. Hoffman and G. Schmer relates to acovalent bonding method involving the use of "soft" hydrogel surfaceswherein radiation grafting is employed with a reactable compoundselected from polymers and copolymers on an inert polymeric substrateand thereafter a biologically active compound is chemically bound to thereactable compound. "Soft" gel-like surfaces are not appropriate fordevices such as catheters or other medical devices which require a"hard" Polymer surface. The "soft" hydrogel or hydrophilic surface ofthe Hoffman et al. patent would be subject to being stripped offcatheters and in case of other blood contact devices, be devoid of themechanical properties required. "Hard" polymers would provide themechanical strength required in such applications.

U.S. Pat. No. 4,326,532 to Hammar discloses a layered medical articlehaving an antithrombogenic surface wherein a natural or syntheticpolymeric substrate is reacted with chitosan and the antithrombogen isthen bonded to the chitosan. Hammer discloses on column 3, lines 10 to49 that the antithrombogenic material may be ionically bonded to thechitosan or covalently bonded using boron hydrides.

In contrast to the aforementioned techniques, Larm et al. disclosed in"A New Non-Thrombogenic Surface Prepared by Selective Covalent Bondingof Heparin via A Modified Reducing Terminal Residue," Biomat., Med.Dev., Art. Org.," (283) pages 161-173 (1983) a new method for bindingheparin to artificial surfaces. The procedure described involvedpartially degrading heparin and coupling the fragments through theirreducing terminal units. Heparin was then ionically and covalentlycoupled to different surfaces with best results achieved usingpolyethylenimine containing primary, secondary and tertiary aminogroups.

It would be desirable to provide a material which has excellentbiological and chemical stability towards body fluids, namely blood, andwhich retains its antithrombogenic agent in a permanent andnon-leachable fashion when in contact with blood. It would also bedesirable to provide materials which, while being biocompatible, arealso biofunctional, that is, materials which have biological activity ina variety of functions.

The present invention accomplishes all of these needs by use of aspecific covalently bonded antithrombogenic agent to a solid support.More particularly the invention involves an antithrombogenicpolyurethane polymer having (a) a support substrate; (b) a protonatedamine rich polyurethane-urea bonded to said support substrate and (c) analdehyde containing antithrombogenic agent reacted with the aminefunctionality of said polyurethane-urea to form a covalently bondedantithrombogenic material.

In another embodiment, the present invention involves a process forimparting antithrombogenic activity to polyurethane polymer materialswhich comprises (a) treating the surface of a solid support with asolution of a protonated amine rich polyurethaneurea so that thepolyurethane-urea is bonded to the support substrate; (b) removingsolvent from the treated substrate to form a layer of thepolyurethane-urea upon the support substrate; (c) activating the aminefunctionality on the polyurethane-urea by use of an alkaline buffer toform free amine groups; and (d) reacting the free amine groups with analdehyde containing antithrombogenic agent to covalently bond theantithrombogenic agent to the polyurethane-urea in the presence of areducing agent.

The term antithrombogenic agent or material as used herein refers to anymaterial which inhibits thrombus formation on its surface, such as byreducing platelet aggregation, dissolving fibrin, enhancing passivatingprotein deposition, or inhibiting one or more steps within thecoagulation cascade. Illustrative antithrombogenic material may beselected from the group consisting of heparin, prostaglandins,urokinase, streptokinase, sulfated polysaccharide, albumin and mixturesthereof. The antithrombogenic material may be used in varying amountsdepending on the particular material employed and ultimate desiredeffect. Preferred amounts have generally been found to be less thanabout 5% by weight of the final products and may range from about 0.2%to about 5% by weight.

The support structure used in the invention is not critical and may beselected from a wide variety of materials that are compatible with apolyurethane-urea formulation. Exemplary support surfaces may beprepared from thermoplastic polyurethanes, thermosetting polyurethanes,vinyl polymers, polyethylene, polypropylene, polycarbonates,polystyrenes, polytetrafluoroethylene, polyesters, polyvinyl chloridesand the like. The particular structures do not constitute a criticalaspect of this invention other than to serve as a support substrate forthe antithrombogenic agent. The supports are preferably performed intothe desired shape or structure for the particular application prior totreatment according to the invention. Of significant importance is theability of the support to bind the modified polyurethane-urea compoundwith the antithrombogenic agent in order to effect irreversiblecoupling. It has been found that any support may be used which has anaverage molecular weight different from the polyurethane-urea compoundused to form the coupling complex and which does not dissolve in theorganic solvent for the complex. This distinction is critical to enablebonding of performed supports without deformation while permitting alayer of polyurethane coupler to be bonded to the support structure. Inthis manner, an integral unit is formed which will not easily separateupon use.

The first step in the process of the invention involves treating thesurface of the solid support with a solution of a protonated amine richpolyurethane-urea so that the polyurethane-urea material is bonded tothe support substrate. The polyurethane-urea materials of the inventionmay be selected from a wide variety of compounds prepared by reacting apolyurethane prepolymer with a diamine.

Polyurethane-ureas are known in the art. They are generally made bychain extending the reaction product of a diisocyanate and a highmolecular weight glycol (urethane prepolymer) with a diamine. Withoutbeing limited there to, one particularly preferred procedure of thepresent invention involves adding diamine in excess, that is from about0.6 to 1 mole of diamine and preferably 0.75 to 1 mole for each freeisocyanate group in the prepolymer to produce a polyurethane-urea withprimary amine end groups. Use of ratio's below 0.6 have been foundunsuitable to prepare an amine rich polyurethane-urea compound to enablesufficient reaction with the antithrombogenic agent. Ratios above about1.0 result in the presence of nonreactive excess diamine which must beremoved from the solution for adequate processing.

The urethane prepolymer can be based on a variety of diisocyanates.Suitable diisocyanates include; 1,4-cyclohexane diisocyante;dicyclohexylmethane 4,4'-diisocyanate; xylene diisocyanate;1-isocyanate-3-isocyanatomethyl-3,5,5-trimethylcyclohexane;hexamethylene diisocyanate; 1,4-dimethylcyclohexyl diisocyanate;2,4,4-trimethylhexamethylene diisocyanate; isocyanates such asm-phenylene diisocyanate; mixtures of 2,4-and 2,6hexamethylene-1,5-diisocyanate; hexahydrotolylene diisocyanate (andisomers), napthylene-1,5-diisocyanate; 1-methoxyphenyl -2,4-diisocyanate; diphenylmethane 4,4 -diisocyanate: 4,4'-biphenylenediisocyanate; 3,3 -dimethoxy - 4,4-biphenyl diisocyanate, 3,3'-dimethyl4,4'-biphenyl diisocyanate, and 3,3'-dimethyl diphenylmethane - 4,4diisocyanate and mixtures thereof. The aliphatic and alicyclicdiisocyanates employed in the process of this invention and the productsmade therefrom generally exhibit good resistance to the degradativeeffects of ultraviolet light.

The high molecular weight glycols useful in the present invention may bea polyether diol or polyester diol and range in number average molecularweight from about 400 to about 3,000 and preferably about 500 to about2,000. The low molecular weight glycols may also be used to prepare theprepolymer which materials may have from about 2 to 10 carbon atoms.Exemplary of the low molecular weight glycols which may be employed toprepare polyester polypols are 1,6-hexanediol, neopentyl glycol,trimethylolpropane, ethylene glycol, diethylene glycol, triethyleneglycol, 1,4-butanediol, 1,4-cyclohexanediol, 1,2-propanediol,1,3-propanediol, 1,3-butylene glycol, 1,4-cyclohexane dimethanol,1,6,-hexanediol, and the like, and mixtures thereof.

The polyethers containing at least 2 hydroxyl groups used in accordancewith the invention are also known per se and are obtained, for example,by polymerizing epoxides, such as ethylene oxide, propylene oxide,butylene oxide, tetrahydrofuran, styrene oxide or epichlorohydrin ontheir own, for example, in the presence of BF₃, or by adding theepoxides, optionally in admixture or in succession, to startercomponents containing reactive hydrogen atoms, such as water, alcohols,or amines, for example, ethylene glycol, 1,3- or 1,2-propylene glycol,4,4'-dihydroxy diphenyl propane, aniline, ammonia, ethanolamine orethylene diamine. The most preferred polyether diols are poly(tetramethylene ether) glycols.

The use of trihydric alcohols can be employed when branched polymers aredesired to improve coating properties. Examples are glycerin,trimethyolpropane, adducts of trimethylolpropane or glycerin withethylene oxide, or epsilon-caprolactone, trimethylolethane, hexanetriol-(1,2,6), butanetriol (1,2,4) and pentaerythritol.

Illustrative polyesters may contain hydroxyl groups, for example,reaction products of polyhydric alcohols reacted with divalentcarboxylic acids. It is also possible to use the correspondingpolycarboxylic acid anhydrides or corresponding polycarboxylic acidesters of lower alcohols or mixtures thereof, for producing thepolyesters. The polycarboxylic acids may be aliphatic, cycloaliphatic,aromatic and/or heterocyclic and may optionally be substituted, forexample, by halogen atoms and/or unsaturated. Examples of polycarboxylicacids of this kind include succinic acid, adipic acid, suberic acid,azelaic acid, sebacic acid, phthalic acid, phthalic acid anhydride,tetrachlorophthalic acid anhydride, endomethylene tetrahydrophthalicacid anhydride, glutaric acid anhydride, maleic acid, maleic acidanhydride, fumaric acid, dimeric and trimeric fatty acids such as oleicacid, optionally in admixture with monomeric fatty acids, terephthalicacid dimethyl ester and terephthalic acid bis-glycol ester. Examples ofsuitable polyhydric alcohols are ethylene glycol, 1,2-and 1,3-propyleneglycol, 1,4- and 2,3-butylene glycol, 1,6-hexanediol, octanediol,neopentyl glycol, cyclohexane dimethanol (1,4-bis-hydroxy methylcyclohexane), 2-methyl-1,3-propanediol, also diethylene glycol,triethylene glycol, tetraethylene glycol, polyethylene glycols,dipropylene glycol, polypropylene glycols, dibutylene glycol andpolybutylene glycols. Polyesters of lactones, for example,ε-caprolactone or hydroxy carboxylic acids, for example,ω-hydroxycaproic acid, may also be used.

The prepolymer is prepared by heating polyols and diisocyanate withagitation in solvent under an inert atmosphere to 60°-100° C. The ratioof NCO to hydroxyl (OH) groups in the prepolymer is from 1.5 to 2:1 witha ratio of 2:1 preferred. The higher NCO to OH ratio limits themolecular weight of the prepolymer and results in higher levels of aminefunctionality from the diamine reaction later.

The diol molecular weight can vary from 400-3000 molecular weight.Molecular weights of about 800 to about 1500 give a combination of goodfilm formation with adequate levels of amine functionality at the end ofthe reaction sequence. A catalyst may be employed but is not required.The reactants are heated for a period sufficient to react all thehydroxyl groups. The reaction time is generally 2-6 hours, howevercatalysts may shorten the reaction time to as little as 5 minutes.Suitable catalysts include tin salts such as dibutyltin dilaurate,stannous octoate or tertiary amines.

The prepolymer reaction is preferably carried out in solvent and in asolvent which is unreactive to NCO. Alternatively, the prepolymer may beformed neat and solvent added after the prepolymer is formed. Convenientsolvents used in preparation of the prepolymer are aromatichydrocarbons, ketones, esters, methylene chloride or tetrahydrofuran.Certain solvents have potential reactivity with amines and thereforemust be evaporated prior to the addition of amines; examples of suchsolvents include ketones and methylene chloride.

A diamine solution is made by dissolving the amine in an appropriatesolvent. Isopropanol was selected because the diamine dissolves (ordisperses) readily in it and it is a secondary alcohol with a lowprobability of competing for available NCO groups with the amine groups.One particularly preferred final solvent mixture of toluene-isopropanol(2:1 by wt.) has the ability to solvate the highly polarpolyurethane-urea.

In addition to isopropanol, methanol, ethanol, propanol, butanol,isobutanol, tert-butanol and diacetone alcohol or mixtures of alcoholsmay also be used.

Amines useful for this invention are: ethylene diamine, 1,3-propylenediamine, 1-4 butanediamine, 1-6 hexanediamine, 1,7-heptanediamine,1,8-octanediamine, 1,9-nonanediamine, 1,10-decanediamine,1,12-dodecanediamine, piperazine, phenylene diamine, tolylene diamine,hydrazine, methylene bis aniline, methylene bis 4 aminocyclohexane,isophorone diamine, 2,2,4 trimethyl-1,6-hexanediamine, menthane diamine,polyoxypropylene diamines and polyoxyethylene-diamines known as"Jeffamines" from Jefferson Chemical Company, U.S.A.

The prepolymer solution may be prepared at a concentration of 10-60%,with 30-40% being preferred (wt/wt). A solution of diamine and solventsuch as isopropanol is made with a concentration of 1-30%, with 5-15%being preferred (net weight). The prepolymer is slowly added to thediamine solution with good stirring, maintaining the temperature at 30°C., in a nitrogen environment. After the reaction solution has beenmixed well and the reaction is complete, a preferred optional procedureinvolves adding an acid slowly to the amine rich polyurethane-ureasolution. A sufficient amount of acid is added to protonate the aminefunctionality of the amine-rich polyurethane-urea. The solutionconcentration is adjusted to an appropriate concentration of 5-50 weightpercent, where 10-30% is preferred and 15-25% is most preferred.

The preferred acid addition technique used according to the inventionprevents premature reaction of the free amine groups with carbon dioxideand other oxidizing agents present in the reaction. This is achieved byconverting the amine groups into salt radicals by reaction with aprotonating acid. Suitable acids include acetic acid, hydrochloric acid,phosphoric acid, formic acid, citric acid, butyric acid, toluenesulfonic acid, methane sulfonic acid and so forth. The reaction permitsthe amine-rich polyurethane-urea compound to be stored for long periods.It has been unexpectedly found that when this protective step was notemployed, a sharp variation in results was evidenced due to variable andoften relatively low amounts of antithrombogenic material bond to thepolyurethane.

The choice of polyurethane-urea solvent for coating the substrate is animportant factor. Many combinations of the previously listed solventscould be found useable by a coatings chemists skilled in the use ofsolubility parameter theory. Although the solvent mixture of toluene andisopropanol has the proper characteristics, many other combinations areuseable.

Other solvents can be substituted by volatilizing the original reactionsolvent and reconstituting to 5-40% by weight where 15-25% is preferred.Exemplary solvents include toluene, methanol, ethanol, propanol,isopropanol, acetonitrite, and the like. The solvent system is importantto the invention but not critical or limiting.

Once prepared, the protonated polyurethane-urea is dispersed ordissolved in a solvent at the appropriate concentration of about 5% toabout 40% and is contacted to form a layer upon the substrate byconventional flow or dip coating processes. Once contacting is complete,the structure is placed in a gaseous environment, preferably nitrogen,to remove the solvent. The structure is then ready for reaction with theantithrombogenic agent. Prior to reacting the protonated amine groupwith the antithrombogenic agent it will be necessary to activate theamine functionality on the polyurethane-urea. Activation may beconveniently performed with an alkaline buffer. The particular buffer isnot critical even though it is preferred that the pH of the buffer beabove about 8.0. Suitable buffers include, but are not limited to,sodium borate, sodium 5:5-diethylbarbiturate-HCl, Clarks and Lubssolution (NaOH, KCl and H₃ BO₃, and sodium bicarbonate.

It is essential according to the invention that the antithrombogenicagent be modified to contain a reactive aldehyde moiety which does notinhibit the bioactivity of the antithrombogenic agent when coupling iscomplete.

The formation of aldehyde containing agents may be achieved byconventional methods. For example when using heparin as theantithrombogenic agent, heparin may be partially depolymerized bydeaminative cleavage with aldehyde inducing compounds such as sodiumperiodate and nitrous acid. This cleavage converts an amine bearingcarbohydrate residue to a 2,5-anhydro-D-mannose residue. One preferredmethod to produce an aldehyde modified heparin involves the reaction ofsodium heparinate with sodium periodate at a pH of between 3-7 with apreferred range of 4-5. The pH of the reaction mixture is maintained byan appropriate buffer. The reaction is carried out with the reactionvessel protected from light with constant stirring. Upon completion ofthe reaction, an excess of glycerin is added to neutralize the remainingunreacted periodate. The aldehyde modified heparin is then optionallydried in a nitrogen environment. The dried aldehyde modified heparin maythen be simply reconstituted in an appropriate acidic buffer of pH3.0-8.0 where 4-7 is preferred and a reducing agent such as sodiumcyanoborohydride is added at weight percent of 1-40%, where 5-30% ispreferred, and 5-15% most preferred. This solution is then exposed tothe amine rich polyurethane-urea coated substrate. The aldehydefunctional groups on the heparin are then reacted with the free aminegroups to give a Schiff base formation that may be reduced to providestable secondary amines. Exemplary reducing agents include sodiumborohydride, sodium cyanoborohydride, and tetrahydrofuran-borane. Thisreaction results in covalently bonding of the antithrombogenic agent tothe polyurethane-urea.

Upon completion of the antithrombogenic coupling reaction, the surfacemay be washed with water to remove loosely bound or unreactedantithrombogenic agent. Washing may be optionally performed with anisotonic solution. The resulting covalently bonded heparin demonstrateshigh antithrombogenic activity as well as permanency andnonleachability.

The invention will be further illustrated by the following nonlimitingexamples. All parts and percentages given throughout the Specificationare by weight unless otherwise indicated.

EXAMPLE 1

This example illustrates the synthesis of a preferred amine richpolyurethane-urea.

29.61 g of trimethylolpropane and 215.14 g of a low molecular weightpolyether polyol such as Teracol™ 650 (poly(oxytetramethylene) glycol)were added together in a mixing vessel (1.0 equivalent of each) andheated at 70° C. After equilibrating, 346.90 g (4.0 equivalents) ofhydrogenated diphenyl methylene diisocyanate was added and mixingcontinued. 0.09 g of dibutyl tin dilaurate (0.015%) was added to themixing solution. After at least 5 minutes of mixing the reactants weretransferred to a 90° C. oven for 60 minutes. After one hour theprepolymer was removed and the percent free NCO groups was titrated andcalculated. Typical values ranged from 8.0-9.5%. The prepolymer was thenpurged with nitrogen gas and stored.

60 g of the previously prepared prepolymer (with NCO content of 8.46%)was added to 120 g of toluene to make a 33% wt/wt solution. A diaminesolution was prepared by adding 14.72 g of 1,6-hexanediamine to 80 g ofisopropanol and 40 g of toluene. The diamine solution was stirredvigorously with a magnetic stir bar. The prepolymer solution was thenadded dropwise to the diamine solution over a two hour period. Thereaction was stirred for an additional two hours. Glacial acetic acid(10 g) was then added dropwise to the reaction mixture. The resultingamine rich polyurethane-urea polymer was then dried with nitrogen gasand finally with vacuum. The amine rich polyurethane-urea polymer wasthen dissolved in methanol to a 20% wt/wt solution for coating.

EXAMPLE 2

This example demonstrates the preparation of an aldehyde modifiedheparin.

Heparin (1.0 g) was added to a sodium acetate buffer which was preparedby dissolving 0.5 g of sodium acetate in 300 ml distilled water. The pHof this solution was then adjusted to 4.5 with glacial acetic acid.

0.1 g of sodium periodate (NaIO₄) was added and the solution was reactedfor 20 minutes in a light protected reaction vessel with constantstirring. Thereafter, 3.0 g of glycerol was added to neutralize anyremaining periodate. The solution was concentrated by drying undernitrogen gas. The final solution was reconstituted to 1% wt/wt.

EXAMPLE 3

This example is illustrative of the preparation of an antithrombogenicsurface according to the present invention.

An amine rich polyurethane-urea polymer of Example 1 was dissolved inmethanol to a 20% wt/wt solution. A polyurethane substrate was coatedwith the amine-rich polyurethane-urea. After coating, the substrate wasplaced in nitrogen atmosphere for 60 minutes at ambient temperature. Thesamples were then placed in sodium borate buffer of pH 9.2, which wasprepared by dissolving 57.21 g of sodium borate in 15 liters ofdistilled water, and stored until reaction with heparin.

The samples were then placed in a mixing vessel and aldehyde-modifiedheparin of Example 2 was added to a concentration of 1%. The reactionwas performed in a pH 4.5 sodium acetate buffer at 50° C. Sodiumcyanoborohydride (0.05 g) was added as a reducing agent. After 2 hoursthe samples were removed and placed in a 3M saline solution to removeany loosely bound or adsorbed heparin. Initial radiolabel assays showedthat 117.2ug±3.4ug of heparin was bound per cm² of surface area. After384 hours washing in a dynamic 3M saline solution, essentially noheparin was leached or lost. The radiolabel assay showed 112.5ug±6ug ofheparin was still bound per cm². This demonstrates the permanency of thecovalent bonded heparin of this invention.

EXAMPLE 4

Various length diamines can be used in the synthesis of the amine richpolyurethane-urea. This example demonstrates the use of an eight carbondiamine.

29.61 g of trimethylolpropane and 215.14 g of a low molecular weightpolyether polyol such as Teracol™ 650 (poly (oxytetramethylene) glycol)were added together in a mixing vessel (1.0 equivalent of each) andheated at 70° C. Thereafter, 346.90 g (4.0 equivalents) of hydrogenateddiphenyl methylene diisocyanate was added. 0.09 g of dibutyl tindilaurate, a catalyst, (0.015%) was added to the mixing solution. Afterat least 5 minutes of mixing the reactants were transferred to a 90° C.oven for 60 minutes. After one hour the prepolymer was removed and thepercent free -NCO groups were titrated and calculated. Typical valuesranged from 8.0-9.5%. The prepolymer was then purged with nitrogen gasand stored.

15 g of the previously prepared prepolymer (with NCO content of 8.16%)was added to 30 g of toluene to make a 33% wt/wt solution. A diaminesolution was prepared by adding 5.09 g of 1.8-octanediamine to 45 g of2:1 isopropanol/toluene (by wt.) solvent mixture. The diamine solutionwas stirred vigorously with a magnetic stir bar. The prepolymer solutionwas then added dropwise to the diamine solution over a two hour period.The reaction was stirred for an additional two hours. 2.23 g of glacialacetic acid was then added dropwise. The resulting amine richpolyurethane-urea was then dried with nitrogen gas and finally withvacuum.

The amine rich polyurethane-urea polymer was then dissolved in propanolto a 15% wt/wt solution for coating.

EXAMPLE 5

This example demonstrates the effectiveness of the present invention inusing longer chain diamines in the amine rich polyurethane-urea and thesubsequent bonding of antithrombogenic agents.

An amine rich polyurethane-urea polymer of Example 4 was dissolved inpropanol to a 15% wt/wt solution. A polyurethane substrate was coatedwith the amine rich polyurethane-urea. After coating, the substrate wasplaced in a nitrogen atmosphere for 60 minutes at ambient temperature.The samples were then placed in sodium borate buffer of pH 9.2 andstored until reaction with heparin.

The samples were then placed in a mixing vessel and aldehyde-modified-heparin, similar to that of Example 2, was added to a concentration of1%. The reaction was performed in a pH 4.5 sodium acetate buffer at 50°C. Sodium cyanoborohydride (0.05 g) was added as a reducing agent. After2 hours the samples were removed and placed in a 3M saline solution toremove any loosely bound or adsorbed heparin. Initial radiolabel assaysshowed that 113.6ug±8.2ug of heparin was bound per cm² of surface area.After 24 hours in a dynamic water wash, the radiolabel assay showed90.7ug±4.9ug of heparin was still bound per cm². This demonstrates thepermanency of the covalent bounded heparin of this invention.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit of scope of the invention and all suchmodifications are intended to be included within the scope of theclaims.

What is claimed is:
 1. A process for imparting antithrombogenic activityto polyurethane polymer materials, which comprises:a. treating thesurface of a solid support with a solution of a protonated amine richpolyurethane-urea so that the polyurethane-urea is bonded to the supportsubstrate; b. removing solvent from the treated substrate to form alayer of the polyurethane-urea upon the support substrate; c. activatingthe amine functionality on the polyurethane-urea with an alkaline bufferto form free amine groups; and d. reacting the free amine groups with analdehyde containing antithrombogenic agent to covalently bond theantithrombogenic agent to the polyurethane-urea in the presence of areducing agent.
 2. The process of claim 1 wherein the protonated aminerich polyurethane-urea is prepared from a polyurethane prepolymer and adiamine.
 3. The process of claim 2 wherein the mole ratio of diamine tofree isocyanate groups in the prepolymer is from about 0.6:1 to 1:1. 4.The process of claim 1 wherein the antithrombogenic agent is heparinwhich is reacted with an aldehyde inducing compound to form aldehydemodified heparin.
 5. The process of claim 1 wherein the aldehydeinducing compound is selected from the group consisting of sodiumperiodate and nitrous acid.
 6. The process of claim 1 wherein thealkaline buffer has a pH greater than about 8.0.
 7. The process of claim1 wherein the polyurethane polymer is selected from thermosettingpolyurethane polymer and thermoplastic polyurethane polymers.